Five families of activated protooncogenes, ras, raf, jun, erbB-2 (neu) and myc have so far been associated with human bronchogenic carcinoma. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumor progression. Overexpression of erbB-2 causes neoplastic transformation of human bronchial epithelial cells. An autocrine growth factor loop between erbB-2 and transforming growth factor alpha may be the mechanism responsible for this neoplastic transformation. Further investigations of raf have revealed that PI-4 kinase is one of its major substrates and may be a downstream effector in the signal transduction pathway of raf. Since the major cause of bronchogenic carcinoma is tobacco smoke, continuing investigations have recently shown that a tobacco-specific N- nitrosamine or cigarette smoke condensate cause neoplastic transformation of human bronchial epithelial cells. An autocrine loop between transforming growth factor alpha and EGF receptor may be involved. This new in vivo/in vitro model of tobacco carcinogenesis should lead to new mechanistic insights and opportunities for intervention and chemoprevention.